Increased mucus elasticity is a major cause of morbidity in patients with chronic airway diseases such as asthma, cystic fibrosis (CF), chronic bronchitis, and patients on mechanical ventilators. Reducing conditions prevail in normal lung secretions, but airway inflammation and administration of supplemental oxygen can shift the airway redox balance. In recent studies, we have shown that oxidation of airway mucus generates disulfide crosslinkages between mucin polymers that increase the elasticity of airway mucus gels. We believe that this mechanism of pathologic mucus formation operates broadly in the upper and lower respiratory tract, because inflammation is invariably associated with alterations in redox balance. In addition, we think the mechanism is relevant in patients who need supplemental oxygen treatment, including those on mechanical ventilators, because we have shown that oxygen increases mucus elasticity. Taken together, our recent results suggest that the oxidative stress that occurs commonly in upper and lower respiratory tract diseases, including during treatment with oxygen, plays an unexpected role in the formation of mucus with pathologically high elasticity. These findings provide a strong rationale for treatment of pathologic mucus in multiple clinical situations with reducing agents. Importantly, such mucolytic therapy will be helpful not just as a reliever of symptoms of upper or lower airway congestion. Experience with rhDNAse and other mucoactive drugs such as hypertonic saline has shown that effective mucolysis is also associated with improvements in other clinical outcomes, such as exacerbation and hospitalization rates.
“N-Acetylcysteine (NAC, “MUCOMYST®”) is a currently available reducing agent that has been used as a mucolytic since the 1960s. The problem is that it has several limitations, including its unstable/volatile nature, which probably contributes to its relatively low potency. In addition, its pKa of 2.2 has disadvantages, particularly for topical or aerosol administration. Further, NAC has a “rotten egg” smell when nebulized and can be irritating when inhaled. For all of these reasons, NAC has not be a particularly successful mucolytic and does not satisfy a large unmet need for novel mucolytic therapies for a wide range of acute and chronic airway disease.
To fill an unmet need, we have synthesized and tested novel reducing agents built on a carbohydrate scaffold. We have evaluated the relative effects of these compounds on the elasticity of airway mucus from human subjects with and without airway disease. To measure elasticity, we have optimized methods using a cone and plate rheometer, including methods to increase signal to noise ratios. To collect airway mucus, we have recruited human subjects who can provide spontaneously expectorated or induced sputum (using hypertonic saline). Disease groups of interest include, inter alia, patients with cystic fibrosis, asthma, chronic bronchitis, bronchiectasis, bronchiolitis, acute and chronic sinusitis, as well as patients who develop “thick” (highly elastic) mucus while being treated with positive pressure mechanical ventilation.